Targeted mRNA therapies treating ARDS

项目摘要/摘要： 这项提案描述了周正杰博士从一名 博士后转为独立研究员。这项建议将基于周博士的过去 在纳米医学和血管研究方面进行了多年的多学科研究。周医生将在 芝加哥大学由一个由世界知名科学家组成的卓越顾问委员会提供咨询，这些专家包括 Yun Fang博士(主要导师)、Matthew Tirrell博士(共同导师)、Jeffrey Hubbell博士、Gökhan Mutlu博士和Dr 格伦·兰德尔。这项提议检验了制造的新型肺靶向脂质体的总体假设 纳米粒以细胞特异性方式传递治疗性信使核糖核酸治疗急性呼吸道疾病 窘迫综合征(ARDS)，是严重流感和SARS-CoV-2感染的主要死亡原因。 目前，ARDS的治疗仍缺乏有效的药物。急性呼吸窘迫综合征的特点是 内皮细胞(ECs)、上皮细胞以及随之而来的失控细胞因子风暴。根据我们最近的调查 靶向血管细胞黏附分子-1(VCAM1)的纳米治疗研究 设计并优化了一种靶向脂质体纳米颗粒，使其能够在细胞内强劲地体内传递mRNA- 具体的方式。利用这个mRNA传递平台，我们建议：(I)通过以下方式促进内皮健康 内皮细胞特异性递送KLF2 mRNA以恢复转录因子KLF2，KLF2在 促进内皮健康和血管系统动态平衡。KLF2在 脂多糖、甲型H1N1流感、SARS-CoV-2和新冠肺炎诱导的小鼠肺；(Ii)激活 上皮特异性递送2‘-5’-寡腺苷合成酶1的上皮细胞天然免疫途径 (OAS1)m RNA通过Oas/核糖核酸酶L途径增强上皮细胞干扰素应答防御 呼吸道病毒感染。我们的数据表明，KLF2mRNA/VCAM1靶向脂质体靶向 能明显减轻甲型H1N1流感和SARS-CoV-2引起的小鼠急性呼吸窘迫综合征。我们的 初步研究表明，OAS1mRNA/上皮靶向脂质体对小鼠炎症肺具有靶向性 并显著降低H1N1病毒复制和肺ARDS。在这个项目中，我将 综合评价VCAM1靶向脂质体修复内皮细胞KLF2的疗效 并减轻(I)H1N1或(Ii)SARS-CoV-2在小鼠模型(Aim 1，K99)和临床上引起的ARDS 潮气式呼吸机(HTV)诱导大鼠ARDS模型(AIM 2，K99/R00)。我会决定如何 上皮靶向转导OAS1激活小鼠先天免疫应答并发挥抗病毒作用 通过OAS1mRNA/上皮靶向脂质体确定其治疗呼吸道病毒的疗效 诱发性ARDS(AIM 3，R00)。成功完成这些项目将提供一种有前景的信使核糖核酸治疗 治疗肺部疾病，并在病毒大流行中提供有效的应答器，而不管病毒的演变和 突变。该信使核糖核酸传递平台具有较强的适应性，可用于多种疾病的治疗。

Project Summary/Abstract: This proposal describes a research and career development plan for Zhengjie Zhou, Ph.D., to transit from a postdoctoral fellow to an independent investigator position. This proposal will be based on Dr. Zhou’s past years of multidisciplinary research in nanomedicine and vascular research. Dr. Zhou will be trained at the University of Chicago by a superb advisory committee of experts who are world-renowned scientists including Dr. Yun Fang (primary mentor), Dr. Matthew Tirrell (co-mentor), Dr. Jeffrey Hubbell, Dr. Gökhan Mutlu and Dr. Glenn Randall. This proposal tests the overall hypothesis of fabricated novel lung-targeting liposomal nanoparticles to deliver therapeutic mRNA in a cell-specific manner for the treatment of acute respiratory distress syndrome (ARDS), which is the major cause of death for severe influenza and SARS-CoV-2 infection. Currently, efficient medicines are still lacking for ARDS therapy. ARDS is characterized by the dysfunction of endothelial cells (ECs), epithelial cells and the following uncontrolled cytokine storm. Based on our recent research about a vascular cell adhesion molecular-1 (VCAM1) targeting nanotherapeutic study, I rationally designed and optimized a targeting liposomal nanoparticle that enables robust mRNA delivery in vivo in a cell- specific manner. Leveraging this mRNA delivery platform, We propose to (i) promote endothelium health by endothelial cell-specific delivery of KLF2 mRNA to restore KLF2, a transcription factor, that plays a key role in facilitating endothelial health and vasculature homeostasis. KLF2 was demonstrated significantly reduced in mice lungs induced by LPS, influenza H1N1, SARS-CoV-2, and COVID-19 patients lungs; (ii) activate epithelial cells innate immune pathway by epithelium-specific delivery of 2’-5’-oligoadenylate synthetase 1 (OAS1) mRNA to augment epithelium interferon (IFN) response through OAS/RNase L pathway to defense respiratory viral infection. Our data demonstrated that KLF2 mRNA/VCAM1-targeting liposome targeted the inflamed mice lungs endothelium and significantly reduced the ARDS induced by H1N1 and SARS-CoV-2. Our preliminary data demonstrated the OAS1 mRNA/epithelium-targeting liposome targeted the mice inflamed lung epithelium and significantly reduced the H1N1 replication and lung ARDS. In this project, I will comprehensively evaluate the therapeutic potency of VCAM1-targeting liposome to restore endothelial KLF2 and lessen ARDS induced by (i) H1N1, or (ii) SARS-CoV-2 in mouse models (Aim 1, K99), and in a clinically relevant rat ARDS model induced by high-tidal ventilation (HTV) (Aim 2, K99/R00). I will determine how epithelium-targeted delivery of OAS1 activates the innate immune response and exerts antiviral effects in mice by OAS1 mRNA/epithelium-targeting liposome and will determine its therapeutic effect to treat respiratory virus induced ARDS (Aim 3, R00). Successful complete these projects will provide a promising mRNA therapeutic treating lung disease and provide an “effective responder” in viral pandemics regardless of virus evolution and mutation. This mRNA delivery platform is adaptable and potentially beneficial for various diseases treatment.